Human subjects who are dependent on methamphetamine (MA) exhibit functional and structural abnormalities within frontostriatal circuitry that most likely contribute to behavioral sequelae of MA abuse. Still little is known about the specific neurochemical adaptations that result from MA abuse and how they contribute directly to impaired neurobehavioral function. Project 3 will employ a non-human primate model of MA dependence to explore the neurochemical mechanisms contributing to impaired response inhibition (as indexed by a reversal learning task) that results from drug exposure (Aim 1). Using both in vivo and ex vivo measures of brain catecholamine function, we will generate insights about the molecular and neurochemical adaptations that contribute directly to functional brain abnormalities revealed in Project 1. These studies will then be extended in two important ways. First, we will explore the mechanisms of action of modafinil, a drug that improves response inhibition in humans and which may, through this mechanism, have therapeutic efficacy in the treatment of stimulant dependence. We will deliver modafinil to control and MA-experienced monkeys and will test the hypothesis that this agent exerts pro-cognitive effects by indirect stimulation of a-2 adrenergic receptors (Aim 2). These complex pharmacological experiments, which are not readily performed in human subjects, will allow us to define a mechanism of action for modafinil and will, in turn, provide a greater understanding of how modafinil produces specific behavioral effects being studied in Projects 1 and 2. Our final goal is to identify more specific targets for pharmacological interventions. As noted above, modafinil may produce indirect stimulation of a-2 adrenergic receptors and multiple lines of evidence now supports the notion that direct a-2 adrenoceptor agonists can improve cognition. We will therefore conduct experiments to test the idea that selective activation of a-2 receptors facilitates response inhibition in MA-exposed monkeys (Aim 3);these results will be compared with effects of subtype-specific dopamine receptor agonists or antagonists, based upon direct evidence supporting their involvement in reversal learning. These experiments have the potential to drive a new phase of medication evaluation in a mature translational research center. Through these Aims, Project 3 proposes to provide a mechanistic foundation for clinical data and to direct future hypothesis testing in clinical populations.